In this proposal we seek to evaluate efficacy of tetrandrine as a novel targeted agent against prostate cancer in pre-clinical model systems. Altered AR signaling is known to play a major role in prostate cancer as well as progression of PCa to Castrate resistant phenotype. While screening for natural compounds for effects against prostate cancer cell growth, we found tetrandrine (Tet) to have selective effects against AR positive PCa cells. Tetrandrine (Tet), an active ingredient isolated from Stephania tetrandra is known to exhibit a broad range of pharmacological actions, and we are the first group to observe its effects against prostate cancer. In preliminary studies presented in this application, we also observed Tet, when injected to mice inhibited the growth of human prostate cancer xenografts in these mice, and dramatically decreased tumor volume. Tet inhibited Prostate Specific Antigen (PSA) synthesis and secretion, blocked cell cycle progression and growth of human PCa cells in culture, induced apoptosis, and inhibited cell migration and invasion, suggesting a direct effect of this compound on the neoplastic process. Based on these exciting preliminary data we hypothesize that Tetrandrine (Tet) targets Androgen Receptor signaling to modulate multiple molecular events in PCa cells that are probably interrelated, such as PSA expression, cell survival and anti-apoptotic signaling and deregulated cell cycle progression involved in uncontrolled PCa growth and malignant progression. As such, Tet may serve as a novel agent for prevention, growth control and therapy of PCa. In the current proposal we will conduct basic and pre-clinical research on Tet with an aim to understand the mechanisms of action against prostate cancer. These objectives will be achieved in three specific aims: Aim 1, is to evaluate the effects of Tet on modulation of Androgen Receptor signaling in prostate cancer cells and to study specific molecular mechanisms by which Tet inhibits Prostate Specific Antigen (PSA); Aim 2, is to define, characterize, and establish molecular mechanism of the inhibitory effect of Tet on cell cycle progression and promotion of apoptosis in PCa cells.; Aim 3, is to evaluate efficacy of Tet against androgen responsive and castrate resistant human PCa cell derived mouse Xenograft models in vivo. We anticipate that proposed studies, together with our preliminary data, will identify Tet as a mechanism-based agent for the prevention, growth control and therapy of PCA, and will establish in vivo efficacy of Tet in pre-clinical human PCa cell derived xenograft models. It is important to emphasize here that an estimated 40,000 men die of Prostate cancer every year in the US. Work proposed in this application, will contribute to development of a novel AR targeted therapy that may translate into an effective treatment regiment against prostate cancer and is therefore, highly relevant to the mission of NCI/NIH.